Wound and mucous membrane disinfectant

ABSTRACT

Aqueous wound and mucous membrane disinfectant containing a) octenidine dihydrochloride, and b) one or more active ingredients selected from the group ethanol, 1-propanol, 2-propanol, undecylene amidopropyl trimonium methosulfate, 3-(4-chlorophenoxy)-1,2-propanediol and/or sodium hydroxymethylglycinate and c) glycerin and/or 1,2-diols having 3 to 10 carbon atoms, and d) optionally surfactants, emulsifiers, solubilisers, pH regulators, dyestuffs, perfumes and/or thickeners, the agent being free of phenoxyethanol, phenoxypropanol, phenoxyisopropanol and organic acids.

The present invention relates to an aqueous wound and mucous membranedisinfectant on the basis of octenidine dihydrochloride, which containsfurther ingredients from the group ethanol, propan-1-ol, propan-2-ol,undecylene amidopropyl trimonium methosulfate, sodiumhydroxymethylglycinate, and 3-(4-chlorophenoxy)-1,2 propanediol. Thedisinfectant according to the present invention has a pH value of from 5to 7 and is free of phenoxyethanol, phenoxypropanol, phenoxyisopropanoland organic acids.

A wound and mucous membrane disinfectant should primarily meet certainmicrobiological requirements, which are described, for example, in F.-A.Pitten, H.-P. Werner, A. Kramer, “A standardized test to assess theimpact of different organic challenges on the antimicrobial activity toantiseptics,” Journal of Hospital Infection (2003) 55, 108-115. However,increasing importance is also being attached to the wound, skin ormucous membrane tolerance of a corresponding disinfectant.

Most of the active ingredients hitherto customary exhibit substantialdeficits in terms of their tolerance. Iodine and PVP-iodine frequentlytrigger allergies with hypersensitivity, moreover, the skin is stronglycolored and iodine, particularly from alcoholic solutions, penetratesthrough the skin and even more markedly through the mucous membrane,which can lead to hyperthyroidosis and even iodism in sensitive persons.Although these side effects are slighter with PVP-iodine, they arelikewise manifest.

In addition to iodine and PVP-iodine and the alcohols, chlorhexidine andsalts thereof are the most important active ingredients in antisepticsworldwide, although these compounds are viewed critically from atoxicological standpoint. Chlorhexidine is positive in the Ames Test andin the DNA Repair Test. Both results indicate a mutagenic potential. Thebreakdown products 4-chloraniline and 4-chlorophenyl isocyanate have agreat affinity to the skin and concentrate there with frequent use.Triclosan, a chlorinated phenol, penetrates through the skin to a greatextent and is a potential dioxin former.

Octenidine dihydrochloride is known as an active ingredient in mucousmembrane and wound antiseptics and can be described by the limitingstructure formulae below:

The raw material octenidine dihydrochloride has a good microbicidaleffectiveness with relatively good tolerance. In DE 39 25 540 C1, anaqueous mucous membrane antiseptic is described, which containsphenoxyethanol and/or phenoxypropanol in addition to octenidinedihydrochloride to increase effectiveness. A preparation of this type iscommercially available, e.g., under the name “Octenisept” and is oftenused in gynecology and andrology. However, recent tests have shown thatthe combination of octenidine dihydrochloride and phenoxyethanol has ahigh cytotoxicity, so that considerable reservations are justifiedregarding use on open wounds.

In WO-02/069874-A1 corresponding to DE 101 09 925-A1, wound and mucousmembrane disinfectants are therefore described which, in addition tooctenidine dihydrochloride, now contain ethanol and a physiologicallytolerated organic acid instead of the above-referenced combination. Thefollowing are cited by way of example as organic acids: lactic acid,glycolic acid, malonic acid, succinic acid, malic acid, tartaric acid,or citric acid. The pH value of these solutions is 2.5 to 3.0. Acidpreparations in this very low range can definitely be tolerated withinfrequent use, but represent a noxa with longer-term application.

Basically all microbicidal active ingredients have a certain irritativepotential, to which the mucous membranes react with particularsensitivity.

The object of the invention was therefore to develop a wound and mucousmembrane disinfectant based on octenidine dihydrochloride, which on theone hand meets the microbicidal requirements—particularly with respectto the effectiveness regarding Candida albicans—but on the other handhas a more favorable pH value compared with the formulas of the priorart and thus a better wound, skin or mucous membrane tolerance.

Completely surprisingly and unforeseeable by one skilled in the art,these objects—particularly regarding the effectiveness with respect toCandida albicans—are met by an aqueous wound and mucous membranedisinfectant containing

-   -   a) octenidine dihydrochloride,    -   b) one or more active ingredients selected from the group        ethanol, 1-propanol, 2-propanol, undecylene amidopropyl        trimonium methosulfate, 3-(4-chlorophenoxy)-1,2-propanediol        and/or sodium hydroxymethylglycinate,    -   c) glycerin and/or 1,2-diols having from 3 to 10 carbon atoms,        and    -   d) optionally surfactants, emulsifiers, solubilisers, pH        regulators, dyestuffs, perfumes and/or thickeners.    -   the agent being free of phenoxyethanol, phenoxypropanol,        phenoxyisopropanol and organic acids.

Particularly preferred components according to the invention accordingto b) are 1-propanol and ethanol. Particularly preferred ingredientsaccording to the invention according to c) are glycerin,1,2-propanediol, 1,2-butanediol, 1,2-pentanediol and/or 1,2-hexanediol.

It is advantageous for the purposes of the present invention to selectthe content of octenidine dihydrochloride from the range of 0.05 to 0.2%by weight. Particularly preferably, the content of octenidinedihydrochloride is approx. 0.1% by weight, in order to achieve a verygood microbicidal effectiveness with at the same time excellent skintolerance.

It is preferred for the purposes of the present invention if the woundand mucous membrane disinfectant according to the invention contains

-   a) 0.05 to 0.2% by weight of octenidine dihydrochloride and-   b) respectively 0.5 to 15.0% by weight of 1-propanol and/or    2-propanol and/or ethanol and/or 0.5 to 5.0% by weight of undecylene    amidopropyl trimonium methosulfate and/or 0.05 to 0.5% by weight of    sodium hydroxymethylglycinate and/or 0.03 to 0.3% by weight of    3-(4-chlorophenoxy)-1,2-propanediol and-   c) 0.2 to 3.0% by weight of glycerin and/or 1,2-diols.

A wound and mucous membrane disinfectant according to the invention isparticularly preferred which consists of:

-   a) 0.05 to 0.15% by weight of octenidine dihydrochloride-   b) 3.0 to 12.0% by weight of ethanol-   c) 0.3 to 1.0% by weight of glycerin (85% by weight),-   d) water to 100% by weight.

Furthermore, a wound and mucous membrane disinfectant is particularlypreferred according to the invention having

-   a) 0.05 to 0.15% by weight of octenidine dihydrochloride,-   b) 2.0 to 6.0% by weight of 1-propanol,-   c) 0.3 to 1.0% by weight of glycerin (85% by weight)-   d) water to 100% by weight.

The wound and mucous membrane disinfectants according to the inventioncan in addition contain other substances such as dyestuffs, perfumes,emulsifiers, solubilizers, pH regulators, thickeners and/or surfactants.Preferably according to the invention, only those substances are takeninto consideration for this purpose that have no or only a very lowadditional irritative potential.

This requirement naturally applies particularly to the surfactants andemulsifiers. Surfactants and emulsifiers are accordingly particularlysuitable for an application for the purposes of the present inventionwhich show no or only a very low irritative potential in the red bloodcell test (RBC test) code 11035 and/or in the hen's egg testchorioaallantoic membrane code 11087 (HET-CAM test). With regard to amore exact gradation between the surfactants and emulsifiers, referenceis thereby made, inter alia, to the relevant literature on the abovetopic.

Particularly advantageously according to the invention only smallamounts—if any—of surfactants and emulsifiers which are very welltolerated by mucous membranes should be used, since otherwise, interalia, an excessive irritation of the mucous membranes may occur.

Surfactants that are suitable and accordingly advantageously to be usedfor the purpose of the present invention are, for example, ethoxylatedglyceryl palmitate (INCI name: PEG-200 hydrogenated glyceryl palmate),ethoxylated sorbitan laurate (INCI: PEG-80 sorbitan laurate),ethoxylated glyceryl isostearate (INCI: PEG-90 glyceryl isostearate),ethoxylated lauryl alcohol (INCI: laureth-2) or also betaines such as,e.g., cocamidopropyl betaine (INCI), a concentration between 0 and 1.0%by weight having proven advantageous. With regard to the emulsifiers,reference is made by way of example to the ethoxylated fatty alcohols oralso fatty acid esters (INCI: ceteareth-20, glyceryl stearate).

The wound and mucous membrane disinfectants according to the inventionare clear solutions with a pH value of from 5 to 7. This pH valueresults, for example, in the particularly preferred formula “by itself,”as it were. In other cases it may be necessary to adjust the pH valueaccordingly. According to the invention, aqueous sodium hydroxide orphosphoric acid have proven useful for this purpose.

The wound and mucous membrane disinfectants can advantageously alsocontain thickeners for the purpose of the present invention. Syntheticpolymers on a polyacrylic acid basis or natural thickeners, such asxanthan gum or modified natural types of thickeners, such as, e.g.,cellulose derivatives, are preferably to be used according to theinvention.

The wound and mucous membrane disinfectant according to the inventioncan be used in different application forms, e.g., per se (i.e., in theform of an aqueous solution), as a gel or as an impregnation solutionfor wipes and/or bandages. However, the wound or mucous membranedisinfectant for the purpose of the present invention can furthermorepreferably also represent the aqueous phase of an emulsion thatfurthermore contains as oil phase those lipids that are known to beparticularly well tolerated by wounds and mucous membranes, such as,e.g., natural oils or modified oils and fats (e.g., almond oil,hydrogenated castor oil).

The subject of the present invention are therefore also O/W or W/Oemulsions—e.g., in the form of a cream, lotion or a spray—which comprisethe aqueous mucous membrane disinfectant.

The present invention is described in more detail by the followingexamples, but without being limited thereby.

EXAMPLES

Raw materials 1 2 3 4 5 6 7 8 9 10 11 12 Octenidine di- 0.1 0.1 0.1 0.050.15 0.1 0.1 0.1 0.05 0.2 0.1 0.1 hydrochloride Ethanol (99% by weight)10.0 12.0 3.0 7.0 7.0 15.0 1-Propanol 4.0 3.0 15.0 2-Propanol 4.0 2.01.0 Undecylene 2.1 4.1 1.1 amidopropyl trimonium methosulfate Sodium0.05 0.5 hydroxymethylglycinate 3-(4-Chlorophenoxy)-1,2- 0.03 0.3propanediol Glycerin (85% by weight) 0.5 0.5 0.5 1.5 3.0 1.5 0.5 0.5 0.51,2-Pentanediol 1.0 0.5 0.2 3.0 NaOH solution Var. Var. Var. Var. Var.Var. Var. Var. Var. Var. Var. Var. Phosphoric acid solution Var. Var.Var. Var. Var. Var. Var. Var. Var. Var. Var. Var. Water ad ad ad ad adad ad ad ad ad ad ad 100 100 100 100 100 100 100 100 100 100 100 100Quantities in % by weight

Tolerance tests were carried out on scarified skin. It was shown therebythat the wound and mucous membrane disinfectants according to theinvention are better tolerated than the preparations of the prior art.

1.-12. (canceled)
 13. An aqueous wound and mucous membrane disinfectant,wherein the disinfectant comprises (a) octenidine dihydrochloride; (b)one or more active ingredients selected from ethanol, 1-propanol,2-propanol, undecylene amidopropyl trimonium methosulfate,3-(4-chlorophenoxy)-1,2-propanediol and/or sodiumhydroxymethylglycinate; and (c) at least one of glycerin and a 1,2-diolhaving from 3 to 10 carbon atoms, the disinfectant being free ofphenoxyethanol, phenoxypropanol, phenoxyisopropanol and organic acids.14. The disinfectant of claim 13, wherein the disinfectant has a pHvalue of from 5 to
 7. 15. The disinfectant of claim 13, wherein (b)comprises one or more of ethanol and 1-propanol.
 16. The disinfectant ofclaim 13, wherein (c) comprises at least one of glycerin,1,2-propanediol, 1,2-butanediol, 1,2-pentanediol and 1,2-hexanediol. 17.The disinfectant of claim 13, wherein the disinfectant comprises (a)from 0.05% to 0.2% by weight of octenidine dihydrochloride; (b) one ormore of (i) from 0.5% to 15.0% by weight of one or more of 1-propanol,2-propanol and ethanol (ii) from 0.5% to 5.0% by weight of undecyleneamidopropyl trimonium methosulfate (iii) from 0.05% to 0.5% by weight ofsodium hydroxymethylglycinate and (iv) from 0.03% to 0.3% by weight of3-(4-chlorophenoxy)-1,2-propanediol; and (c) from 0.2 to 3.0% by weightof at least one of glycerin and a 1,2-diol.
 18. The disinfectant ofclaim 13, wherein the disinfectant consists of (a) from 0.05% to 0.15%by weight of octenidine dihydrochloride; (b) from 3.0% to 12.0% byweight of ethanol; (c) from 0.3% to 1.0% by weight of glycerin (85% byweight); and (d) water to 100% by weight.
 19. The disinfectant of claim13, wherein the disinfectant consists of (a) from 0.05% to 0.15% byweight of octenidine dihydrochloride; (b) from 2.0% to 6.0% by weight of1-propanol; (c) from 0.3% to 1.0% by weight of glycerin (85% by weight);and (d) water to 100% by weight.
 20. The disinfectant of claim 13,wherein the disinfectant further comprises one or more additivesselected from surfactants, emulsifiers, solubilizers, dyestuffs, pHregulators and/or thickeners.
 21. The disinfectant of claim 20, whereinthe disinfectant comprises one or more of ethoxylated glycerylpalmitate, ethoxylated sorbitan laurate, ethoxylated glycerylisostearate, ethoxylated lauryl alcohol and cocamidopropyl betaine. 22.The disinfectant of claim 20, wherein the disinfectant comprises fromabout 0% to 1.0% by weight of one or more surfactants.
 23. Thedisinfectant of claim 20, wherein the disinfectant comprises from about0% to 5.0% by weight of one or more emulsifiers.
 24. The disinfectant ofclaim 20, wherein the disinfectant comprises one or more thickenersselected from polyacrylic, natural and modified natural thickeners. 25.The disinfectant of claim 14, wherein the pH of the disinfectant hasbeen adjusted by one of aqueous sodium hydroxide and phosphoric acid.26. The disinfectant of claim 13, wherein the disinfectant is present asone or more of a liquid, a gel, a cream, a lotion, a spray andimpregnated on a wipe or bandage.
 27. An aqueous wound and mucousmembrane disinfectant, wherein the disinfectant comprises (a) octenidinedihydrochloride; (b) one or more of ethanol and 1-propanol; and (c) atleast one of glycerin, 1,2-propanediol, 1,2-butanediol, 1,2-pentanedioland 1,2-hexanediol, the disinfectant being free of phenoxyethanol,phenoxypropanol, phenoxyisopropanol and organic acids and having a pH offrom 5 to
 7. 28. The disinfectant of claim 27, wherein the disinfectantfurther comprises one or more of ethoxylated glyceryl palmitate,ethoxylated sorbitan laurate, ethoxylated glyceryl isostearate,ethoxylated lauryl alcohol and cocamidopropyl betaine.
 29. Thedisinfectant of claim 27, wherein the disinfectant further comprisesfrom about 0% to 1.0% by weight of one or more surfactants.
 30. Thedisinfectant of claim 29, wherein the disinfectant further comprisesfrom about 0% to 5.0% by weight of one or more emulsifiers.
 31. Thedisinfectant of claim 27, wherein the disinfectant further comprises oneor more thickeners selected from polyacrylic, natural and modifiednatural thickeners.
 32. The disinfectant of claim 27, wherein the pH ofthe disinfectant has been adjusted by one of aqueous sodium hydroxideand phosphoric acid.